This is a multicenter randomized controlled trial (RCT) to test the hypothesis that treatment with a gonadotropin-releasing hormone agonist (GnRH-a) reduces ovarian injury versus placebo in women of reproductive age being treated with cyclophosphamide for severe rheumatic diseases. Women ages 18-40 years who require administration of daily oral or intermittent pulse cyclophosphamide according to evidence-based protocols for treatment of severe rheumatic diseases including lupus nephritis, Wegener's granulomatosis, other forms of pauci-immune vasculitis, and severe interstitial lung disease complicating scleroderma will be entered into the trial. Patients will be enrolled at five academic centers with major clinical programs focused on lupus, vasculitis and scleroderma. GnRH-a or placebo will be administered for 3-6 months depending on the duration of cyclophosphamide therapy. Longitudinal follow-up during the intervention and 6 months post-intervention will assess biomarkers of ovarian reserve, including anti-mullerian hormone (AMH), FSH, and ultrasound measurement of ovarian volume and antral follicle counts. Long-term follow-up is planned to assess menstrual cycle parameters, the number and outcome of pregnancies, and time to ovarian failure. The primary outcome measure will be AMH levels in the GnRH-a vs. placebo groups. AMH is a validated marker of ovarian reserve and fecundability that we have shown to be reduced after cyclophosphamide administration, adjusting for age and cumulative cyclophosphamide dose. This outcome was chosen to enable detection of treatment effect in women who may experience decline in ovarian function but not overt ovarian failure. Secondary outcomes include the effect of GnRH-a on other parameters of ovarian function including FSH, menstrual cyclicity, ovarian volume and antral follicle counts. This will be the first RCT of GnRH-a for ovarian protection during alkylating agent treatment for rheumatic diseases. Advantages of studying the rheumatic disease population include young age and exposure to only one chemotherapeutic agent. A positive result could lead to significantly improved quality of life for many women with rheumatic diseases or cancer treated with cyclophosphamide, by preserving reproductive capacity and preventing premature hormone withdrawal. In addition, this will be the first RCT to test the ability of surrogate markers of ovarian function to predict subsequent development of chemotherapy-induced premature ovarian failure and assess the potentially protective effects of GnRH-a. This information will help guide women and their physicians making decisions regarding use of alkylating agents when preservation of ovarian function is desired. PUBLIC HEALTH RELEVANCE: Premature ovarian failure, or early menopause, is a devastating side effect of some chemotherapies used for the treatment of autoimmune or rheumatic conditions (including lupus, vasculitis, and scleroderma) and cancers (including breast cancer). The proposed clinical trial will evaluate the ability of a drug (leuprolide acetate, which is a gonadotropin-releasing hormone agonist) to protect ovaries in patients receiving a specific type of chemotherapy (cyclophosphamide) for rheumatic diseases. Prevention of premature ovarian failure is important not only to preserve fertility, but also to reduce risk of other health problems associated with early menopause, such as cardiovascular disease, osteoporosis, and overall mortality.